A simple novel approach for detecting blood-brain barrier permeability using GPCR internalization.

AIMS: Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage. However, these procedures are challenging to apply in pups and embryos and may appear difficult to interpret. Here we introduce a novel approach based on agonist-induced internalization of a neuronal G protein-coupled receptor widely distributed in the mammalian brain, the somatostatin receptor type 2 (SST2). METHODS: The clinically approved SST2 agonist octreotide (1 kDa), when injected intraperitoneally does not cross an intact BBB. At sites of BBB permeability, however, OCT extravasates and induces SST2 internalization from the neuronal membrane into perinuclear compartments. This allows an unambiguous localization of increased BBB permeability by classical immunohistochemical procedures using specific antibodies against the receptor. RESULTS: We first validated our approach in sensory circumventricular organs which display permissive vascular permeability. Through SST2 internalization, we next monitored BBB opening induced by magnetic resonance imaging-guided focused ultrasound in murine cerebral cortex. Finally, we proved that after intraperitoneal agonist injection in pregnant mice, SST2 receptor internalization permits analysis of BBB integrity in embryos during brain development. CONCLUSIONS: This approach provides an alternative and simple manner to assess BBB dysfunction and development in different physiological and pathological conditions.

A combined single-stage procedure to treat brain AVM.

Complete resection of brain arteriovenous malformation (AVM) is a surgical challenge, mainly due to risk of intraoperative rupture. The objective of this feasibility study was to analyze complete resection rate at 3 months and clinical outcome at 6 months after treatment of brain AVM by combined single-stage embolization and surgical resection. A retrospective observational study from July 2015 to February 2019 was conducted at the Department of Neurosurgery of Strasbourg University Hospital, France. Decision to treat was taken on the basis of history of AVM rupture, symptomatic AVM, or morphologic risk factors for rupture. Complete resection rate was assessed on postoperative cerebral subtraction angiography at 3 months and clinical outcome at 6 months was evaluated on the modified Rankin Scale (mRS). In the 16 patients treated for symptomatic brain AVM, the rate of complete resection was 75%, resection with residual shunt 18.7%, and incomplete resection with residual nidus 6.3%. Good clinical outcome (mRS=0 or 1) was achieved in 81.3% of patients at 6 months. The transfusion rate was 7.1%. There were procedural complications in 12.5% of patients but no intraoperative ruptures. This combined single-stage procedure allows extensive preoperative embolization of the AVM, facilitating surgical microdissection by identifying the dissection plane and perforating arteries and allowing the operator to work in close contact with the nidus without fear of intraoperative rupture.

Predictive factors of epilepsy in arteriovenous malformation.

OBJECTIVE: Structural epilepsy related to cerebral arteriovenous malformation (AVM) suggests different epileptogenic mechanisms. The aim of our study was to determine factors associated with epilepsy into a retrospective cohort of AVM patients. PATIENTS AND METHODS: Ruptured and unruptured AVM data retrieved from a prospective single center registry (2009-2016) were retrospectively assessed. Demographic, clinical and radiological features were identified in AVM patients with or without epilepsy according to the International League Against Epilepsy classification. RESULTS: Epilepsy concerned 22 out of 80 consecutive patients with AVM (27.5%). Univariate analysis comparing both groups revealed a significant association of different variables with the structural epilepsy: young age (P=0.02), large nidus size (P=0.02), venous dilation (P=0.02), posterior cerebral artery (PCA) feeder (P<0.001) and Spetzler-Martin grade (P=0.02). Based on multivariate analysis, only the PCA feeder was identified (OR=5.2 [95% CI 1.1-24,5], P=0.04). CONCLUSION: PCA feeder for cerebral AVM was significantly associated with structural epilepsy. The hypothesis of a vascular steal phenomenon to the detriment of internal temporal lobe vascularization could be related to the development of epilepsy.

Subclinical haemorrhage in non-functional adenomas.

AIM: The prevalence and risk factors of subclinical haemorrhage on non-functional adenomas (NFA) remain controversial. The primary aim of our study was to assess the incidence of subclinical haemorrhage (SH) and the secondary objectives were to evaluate the risk factors of SH and the impact of SH on pituitary function at diagnosis. PATIENTS AND METHODS: This retrospective transversal analysis included 95 patients between January 2012 and December 2014. The patients included in this series were all adults (>18 years of age), who presented a non-functional adenoma confirmed by an endocrinological evaluation and on dedicated MRI pituitary imaging. Sixty-four patients were eligible for this study. Subclinical haemorrhage was defined by the presence of haemorrhage within pituitary adenoma confirmed by pituitary MRI with no clinical symptoms. A senior neuroradiologist blinded to the diagnosis reviewed all MRI. The population was prospectively divided into two groups based on MRI results (SH group vs. group control) to determine risk factors. RESULTS: SH was diagnosed in 22 patients (34.38%). No risk factors (age, sex, tumor size, chronic hypertension, diabetes mellitus, malignant disease, the use of anticoagulation or antithrombotic medication or Cabergoline treatment) were involved as regards the SH. At the diagnosis, pituitary deficiency was statistically significantly more frequent in the SH group (45.45%) than in the control group (19.04%) (P=0.04). CONCLUSION: The SH within NFA was observed in 34.38% of cases without an association of risk factors.

Diagnosis and suggested treatment against an isolated unilateral rupture of the alar ligament - Concerning one case.

BACKGROUND: An isolated rupture of the alar ligament is a rare occurrence with only a few cases reported in the literature. CASE REPORT: The objective was to report the case of a young man with a unilateral rupture of the alar ligament that we closely monitored, clinically and radiologically, in order to describe the evolution of the alar ligament lesions. CONCLUSION: Radiological diagnosis using cervical MRI and duration of the conservative treatment remain debated and we proposed a close radiological follow-up in order to best understand the nature of these ligament lesions and their evolution following specific treatment.

Reproducibility of R2 * and quantitative susceptibility mapping (QSM) reconstruction methods in the basal ganglia of healthy subjects.

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R2 *). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinson's disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra-subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2 * images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2 * mapping in iron-rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright © 2016 John Wiley & Sons, Ltd.

Encapsulated contrast microbubble radial oscillation associated with postexcitation pressure peaks.

This work combines modeling and experiment to assess encapsulated microbubble oscillations associated with broadband pressure peaks detected after microbubble excitation (postexcitation signals). Data were acquired from albumin-shelled and phospholipid-shelled microbubbles using a passive cavitation detector consisting of a confocally aligned 2.8-MHz transmitter and 13-MHz receiver. Microbubbles in weak solutions were insonified with a 5-cycle pulse at a peak rarefactional pressure of 2.0+/-0.2 MPa. For each microbubble type, at least 100 received signals were identified as individual-microbubble responses. The average broadband noise from signals with postexcitation response was 4.2-7.2 dB higher than from signals without postexcitation. Pressure-time responses for each microbubble type were simulated using the model by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)], with insonification conditions matching the experiment. Increased broadband noise predicted for microbubbles with postexcitation response was consistent with that observed experimentally (4.0-8.9 dB). The model predicted that postexcitation signals occur only when the radial oscillation exceeds both the shell break-up threshold and twice the initial radius (free bubble inertial cavitation threshold).